Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity

Abstract

Natural killer (NK) cells are powerful effector cells that can be directed to eliminate tumor cells through tumor-targeted monoclonal antibodies (mAbs). Some tumor-targeted mAbs have been successfully applied in the clinic and are included in the standard of care for certain malignancies. Strategies to augment the antitumor response by NK cells have led to an increased understanding of how to improve their effector responses. Next-generation reagents, such as molecularly modified mAbs and mAb-cytokine fusion proteins (immunocytokines, ICs) designed to augment NK-mediated killing, are showing promise in preclinical and some clinical settings. Continued research into the antitumor effects induced by NK cells and tumor-targeted mAbs suggests that additional intrinsic and extrinsic factors may influence the antitumor response. Therefore more research is needed that focuses on evaluating which NK cell and tumor criteria are best predictive of a clinical response and which combination immunotherapy regimens to pursue for distinct clinical settings.

Figure 1

Immunocytokine facilitates adhesion of NK cells to tumor cells. This figure, adapted from Buhtoiarov et al. [36], shows the adhesion of M21 human melanoma tumor cells to NKL human NK cells after coincubation for 30 minutes. Tumor cells were prelabeled with CFSE, and NK cells were prelabeled with BODIPY and coincubated in medium alone, with hu14.18 (mAb) alone, soluble IL2, hu14.18 + soluble IL2, or hu14.18-IL2 immunocytokine (IC). The percentage of cells that had formed conjugates was defined as double positive cells as determined by flow cytometry.